Effect of TO901317 on promoting the differentiation of human bone marrow mesenchymal stem cells into dopamine neurons on Parkinson's disease
Abstract Background: Stem cells from different sources could differentiate into dopamine-producing cells and ameliorate behavioral deficits in Parkinson's disease (PD) models. Especially, human bone marrow mesenchymal stem cells (hBMSCs) have many advantages without ethical dispute. Liver X receptors (LXRs) are involved in the maintenance of the normal function of the central nervous system myelin. The previous work of our team have reported the induction of cocktail-induced da phenotypes from adult rat BMSCs by using sonic hedgehog (SHH), fibroblast growth factor 8 (FGF8), basic fibroblast growth factor (bFGF) and TO901317 (agonist of LXRs) with 87.42% of efficiency in 6 days of period of induction. But it did not verify whether the induced cells had the corresponding neural function. Methods: The present study was to investigate the effect of TO901317 on the differentiation of hBMSCs into dopaminergic (DA) neurons. In vitro, the cells were divided into control group, GF group and LXR+GF group. Neuronal markers (Tuj1, Neun and Nestin) and DA neuron markers (tyrosine hydroxylase, TH) were detected to explore the optimal concentration, optimal addition time and optimal induction time of TO901317 to promote hBMSCs differentiation. Determine induced cells’ DA neuron properties by detecting dopamine release. To clarify its underlying mechanisms, the expressions of LXRa, LXRb and ABCA1 were detected. In vivo, male Sprague Dawley (SD) rats were divided into control group, 6-OHDA group (model group) and 6-OHDA+Cells group (cell transplantation group) to observe whether cell transplantation had a therapeutic effect on PD. Results: TO901317 significantly enhanced the differentiation of hBMSCs into DA neurons. Compared to control group and GF group, only the LXR+GF group released dopamine by the result of enzyme linked immunosorbent assay (ELISA). Compared with the control group and GF group, the optimal time for differentiation of hBMSCs treated by 0.5mM TO901317 combined with GF was six days in LXR+GF group. And the maximum induction efficiency of differentiation of hBMSCs into DA neurons was 91.67% in LXR+GF group. After the long-term use of TO901317, LXRα and LXRβ decreased significantly, and ABCA1mRNA increased significantly in LXR+GF group. After induced-cells were transplanted into PD rats, Compared with 6-OHDA group, the expression of TH in the striatum increased significantly, and the behavior of PD rats induced by apomorphine was significantly improved in the 6-OHDA+Cells group.Conclusions: TO901317 promoted differentiation of hBMSCs into DA neurons may be related to activation of LXR-ABCA1 signaling pathway. These data suggested that TO901317 may serve as a potential therapeutic methods for PD.